Submissions for variant NM_024675.4(PALB2):c.3113G>A (p.Trp1038Ter)

gnomAD frequency: 0.00002  dbSNP: rs180177132

Total submissions: 35

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	RCV000114591	SCV003915565	pathogenic	Familial cancer of breast	2023-04-05	reviewed by expert panel	curation	The c.3113G>A (p.Trp1038Ter) variant in PALB2 occurs at the last nucleotide of exon 10. It is predicted to cause skipping of biologically-relevant exon 10, as well as partial deletion of exon 10, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This prediction is confirmed by RT-PCR analysis (PMID: 21285249, 23448497). This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (PALB2 p.Tyr1183*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant is non-functional in multiple different protein assays (PMID 31757951); however due to a lack of positive missense controls with known clinical impact, these protein assays do not meet the requirements for use by the HBOP VCEP. The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls [OR=4.21, 95% CI:1.84 - 9.60] (PMID: 27595995). The highest population filtering allele frequency in gnomAD v2.1.1 is 0.00006665 in the European (Non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1(RNA), PS4, PM5_Supporting).
GeneDx	RCV000212822	SCV000150005	pathogenic	not provided	2020-02-11	criteria provided, single submitter	clinical testing	Observed in multiple individuals with a personal and/or family history of breast cancer and is considered a pathogenic founder variant in the British population (Rahman 2007, Southey 2010, Wong 2011, Teo 2013, Hartley 2014, Southey 2016, Winship 2016); Published functional studies demonstrate a damaging effect: reduced RAD51 foci formation, abnormal cellular localization, diminished homology repair efficiency, weak protein expression (Pauty 2017, Boonen 2019); This variant is associated with the following publications: (PMID: 21165770, 17200668, 21409391, 23471749, 18302019, 19264984, 22241545, 26283626, 24206657, 25099575, 19763819, 26250988, 23787919, 23448497, 26786923, 27621404, 25575445, 28158555, 32081490, 32581362, 25525159, 25225577, 24415441, 23935381, 21932393, 24870022, 20346647, 24556926, 24136930, 24061862, 26534844, 25356972, 17200671, 21182766, 21285249, 26787237, 27547810, 27595995, 28019080, 28135136, 27099641, 26985847, 27296296, 27433846, 26681312, 26315354, 28864920, 28779002, 29431189, 29909963, 30665703, 29961768, 30322717, 31090900, 31757951, 31263054, 29625052, 26689913, 32426482, 31447099, 32832836, 32338768)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000114591	SCV000166660	pathogenic	Familial cancer of breast	2025-01-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp1038*) in the PALB2 gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs180177132, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 17200668, 21182766, 21285249, 23471749). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 126711). Studies have shown that this premature translational stop signal results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (internal data). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000116096	SCV000183829	pathogenic	Hereditary cancer-predisposing syndrome	2022-10-26	criteria provided, single submitter	clinical testing	The c.3113G>A pathogenic mutation (also known as p.W1038*), located in coding exon 10 of the PALB2 gene, results from a G to A substitution at nucleotide position 3113. This changes the amino acid from a tryptophan to a stop codon within coding exon 10. This change occurs in the last base pair of coding exon 10, and has been shown to generate three aberrant mRNA isoforms: one with complete skipping of exon 10 (deletion of 117 bp), another which uses an alternative splice site within exon 10 (out-of-frame deletion of 31 bp) (Casadei S et al. Cancer Res. 2011 Mar;71:2222-9; Teo ZL et al. Breast Cancer Res. 2013 Feb;15:R17; Casadei S et al. Proc Natl Acad Sci U S A, 2019 Dec). In addition, this mutation has been identified in multiple early-onset breast cancer probands with significant breast cancer family histories (Hartley T et al. Hered Cancer Clin Pract. 2014;12:19; Teo ZL et al. Fam. Cancer. 2013 Dec;12:587-95; Rahman N et al. Nat. Genet. 2007 Feb;39:165-7; Wong MW et al. Breast Cancer Res. Treat. 2011 Jun;127:853-9; Zhen DB et al. Genet. Med. 2015 Jul;17:569-77; Nguyen-Dumont T et al. Breast Cancer Res. Treat. 2015 Jan;149:547-54; Thompson ER et al. Breast Cancer Res. 2015 Aug;17:111; Ding YC et al. Fam. Cancer. 2018 Apr;17:187-195). This alteration has also been reported in a kindred with at least two family members affected with pancreatic cancer (Zhen DB et al. Genet. Med. 2015 Jul;17:569-77). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Eurofins Ntd Llc (ga)	RCV000212822	SCV000225072	pathogenic	not provided	2018-03-06	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000116096	SCV000266105	pathogenic	Hereditary cancer-predisposing syndrome	2015-11-20	criteria provided, single submitter	clinical testing
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000114591	SCV000267971	likely pathogenic	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
Color Diagnostics, LLC DBA Color Health	RCV000116096	SCV000292142	pathogenic	Hereditary cancer-predisposing syndrome	2024-01-17	criteria provided, single submitter	clinical testing	This variant causes a nonsense mutation in exon 10 and is also predicted to disrupt splicing at the intron 10 splice donor site in the PALB2 gene. RNA studies have reported that this variant causes splicing defects resulting in an in-frame deletion of exon 10 or exons 9 and 10, impacting the WD40 domain of PALB2, or an out-of-frame transcript due to the use of a cryptic donor site within exon 10 that results in a premature translational stop signal. Normally spliced transcript from the mutant allele has a nonsense mutation due to the coding sequence change (PMID: 21285249, 23448497, 31843900). This variant has been observed in over a dozen individuals affected with early-onset breast cancer with positive history of breast and other cancers (PMID: 17200668, 21182766, 21285249, 22241545, 23471749, 25225577, 28864920; DOI: 10.1016/j.gimo.2023.100849), an individual affected with familial pancreatic cancer (PMID: 25356972), and in two individuals affected with ovarian cancer and two unaffected individuals (PMID: 26315354). This variant has been detected in a breast cancer case-control meta-analysis in 31/60466 cases and 6/53461 unaffected individuals with an estimated odds ratio of 4.57 (95% CI 1.906 to 10.955) (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010150). This variant has been shown to segregate with breast cancer in families (PMID: 21182766, 26534844). This variant has been identified in 17/282756 chromosomes in the general population by the Genome Aggregation Database (gnomAD), predominantly in non-Finnish Europeans and also in African-Americans. Loss of PALB2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Counsyl	RCV000114591	SCV000488411	pathogenic	Familial cancer of breast	2016-03-18	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212822	SCV000601775	pathogenic	not provided	2024-01-09	criteria provided, single submitter	clinical testing	The PALB2 c.3113G>A (p.Trp1038*) variant causes the premature termination of PALB2 protein synthesis. This variant has been reported in the published literature in individuals with breast cancer (PMID: 33758026 (2022), 26283626 (2015), 25225577 (2014), 24206657 (2013), 21409391 (2011)), prostate cancer (PMID: 32853339 (2021), 27433846 (2016)), and pancreatic cancer (PMID: 25356972 (2015), 19264984 (2009)). Additionally, splicing studies have shown that this variant produces three alternate transcripts which either result in premature termination of protein synthesis or deletion of exon 10 (PMID: 23471749 (2013) and 21285249 (2011)). The frequency of this variant in the general population, 0.00012 (3/24968 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588093	SCV000699583	pathogenic	Hereditary breast ovarian cancer syndrome	2017-05-08	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000114591	SCV000840027	pathogenic	Familial cancer of breast	2017-04-03	criteria provided, single submitter	clinical testing	This c.3113G>A (p.Trp1038*) variant has previously been reported in 16 (out of 4,178 total) patients with breast cancer [PMID 17200668, 21285249, 25575445, 23448497, 26283626, 21409391, 23471749]. The cumulative risk for carrier of this variant was estimated as 91% by age 70 with a median age of onset of 42 years old reported in an Australian population [PMID 23471749]. This c.3113G>A is located in exon 10 of the PALB2 gene at the exon/intron junction with intron 10. Transcripts analysis showed that this variant not only produces a stop codon at amino acid position 1038 but also produces two additional PALB2 transcripts including an alternative splicing and a complete deletion of exon 10, all three leading to a loss of function of the protein [PMID 23471749]. The c.3113G>A (p.Trp1038*) variant has been observed in two Europeans and one African individual at the heterozygous state in the ExAC population database (http://exac.broadinstitute.org/variant/16-23632683-C-T). It is thus interpreted as a pathogenic variant.
Illumina Laboratory Services, Illumina	RCV004528792	SCV000914711	pathogenic	PALB2-related disorder	2018-09-19	criteria provided, single submitter	clinical testing	The PALB2 c.3113G>A (p.Trp1038Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. Across a selection of the available literature, the c.3113G>A (p.Trp1038Ter) variant has been identified in a heterozygous state in at least 21 probands from 13 unrelated families (Rahman et al. 2007; Southey et al. 2010; Teo et al. 2013; Hartley et al. 2014). Affected individuals were found to have a variety of cancers including breast, ovarian, and pancreatic. The p.Trp1038Ter variant was absent from 1724 healthy control subjects and is reported at a frequency of 0.000125 in the African population of the Genome Aggregation Database. Experimental studies on RNA isolated from patient derived lymphoblastoid cell lines have shown that the p.Trp1038Ter variant caused altered splicing (Casadei et al. 2011; Teo et al. 2013). Although this variant has not been reported in any probands with Fanconi anemia, it is known that PALB2 heterozygous variants can also confer carrier status for Fanconi anemia. Due to the potential impact of stop-gained variants and the evidence from the literature, this variant is classified as pathogenic for PALB2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Academic Department of Medical Genetics, University of Cambridge	RCV000116096	SCV000992220	pathogenic	Hereditary cancer-predisposing syndrome	2018-01-26	criteria provided, single submitter	research	Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity.
Genetic Services Laboratory, University of Chicago	RCV000212822	SCV002069665	pathogenic	not provided	2021-01-15	criteria provided, single submitter	clinical testing	DNA sequence analysis of the PALB2 gene demonstrated a sequence change, c.3113G>A, located in the consensus splice site of the exon. Functional studies have demonstrated that this sequence change affects normal splicing and creates different PALB2 transcripts in lymphoblastoid cells derived from individuals with breast cancer, including one with complete skipping of exon 10 (deletion of 117 bp), another with an alternative splice site within exon 10 (out-of-frame deletion of 31 bp), and one which results in an immediate stop at amino acid position 1038 (p.Trp1038*) (PMID: 21285249, 23448497). The p.Trp1038* change has been reported in individuals and families with breast cancer, with evidence of co-segregation with disease (PMID: 17200668, 21182766, 21285249, 23471749). This sequence change has been observed in the gnomAD database with a frequency of 0.011% in the European sub-population (dbSNP rs180177132). These collective evidences suggest that this sequence change is pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV000212822	SCV002502281	pathogenic	not provided	2022-02-09	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000114591	SCV002583786	pathogenic	Familial cancer of breast	2022-07-11	criteria provided, single submitter	clinical testing	PVS1, PS4
Myriad Genetics, Inc.	RCV000114591	SCV004019609	pathogenic	Familial cancer of breast	2023-03-31	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003389455	SCV004101687	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 5	2023-11-13	criteria provided, single submitter	clinical testing	A known pathogenic mutation was detected in the PALB2 gene (c.3113G>A).This sequence change creates a premature translational stop signal (p.Trp1038*) in the PALB2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 17200671, 17200672, 24136930, 25099575). This variant is present in population databases (rs180177132, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 21165770, 17200668, 21409391, 23471749, 18302019, 19264984, 22241545, 26283626, 24206657, 25099575, 19763819, 26250988, 23787919, 23448497, 26786923, 27621404, 25575445, 28158555, 32081490, 32581362, 25525159, 25225577, 24415441, 23935381, 21932393, 24870022, 20346647, 24556926, 24136930, 24061862, 26534844, 25356972, 17200671, 21182766, 21285249, 26787237, 27547810, 27595995, 28019080, 28135136, 27099641, 26985847, 27296296, 27433846, 26681312, 26315354, 28864920, 28779002, 29431189, 29909963, 30665703, 29961768, 30322717, 31090900, 31757951, 31263054, 29625052, 26689913, 32426482, 31447099, 32832836, 32338768) . It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 126711). Published functional studies demonstrate a damaging effect, abnormal cellular localization, diminished homology repair efficiency, weak protein expression (PMID: 21285249, 23448497). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000114591	SCV004202029	pathogenic	Familial cancer of breast	2024-03-29	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000116096	SCV004228120	pathogenic	Hereditary cancer-predisposing syndrome	2023-08-01	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492443	SCV004239562	pathogenic	Breast and/or ovarian cancer	2022-09-13	criteria provided, single submitter	clinical testing
Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service	RCV004577322	SCV005061418	pathogenic	NICE approved PARP inhibitor treatment	2024-04-30	criteria provided, single submitter	clinical testing	PVS1,PS4
Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service	RCV004584192	SCV005068345	pathogenic	Inherited ovarian cancer (without breast cancer)	2024-05-03	criteria provided, single submitter	clinical testing	PVS1,PS4
Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service	RCV004584191	SCV005068369	pathogenic	Inherited breast cancer and ovarian cancer	2024-05-14	criteria provided, single submitter	clinical testing	PVS1,PS4
NHS Central & South Genomic Laboratory Hub	RCV004584191	SCV005395909	pathogenic	Inherited breast cancer and ovarian cancer	2024-11-12	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000212822	SCV005414342	pathogenic	not provided	2024-07-23	criteria provided, single submitter	clinical testing	PM5_supporting, PS4, PVS1
Fulgent Genetics, Fulgent Genetics	RCV005016387	SCV005646463	pathogenic	Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3; Breast-ovarian cancer, familial, susceptibility to, 5	2024-01-31	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV003389455	SCV005913262	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 5	2020-04-29	criteria provided, single submitter	clinical testing
OMIM	RCV003389455	SCV000190693	risk factor	Breast-ovarian cancer, familial, susceptibility to, 5	2013-02-28	no assertion criteria provided	literature only
Pathway Genomics	RCV000114591	SCV000207350	pathogenic	Familial cancer of breast	2014-11-06	no assertion criteria provided	clinical testing
Leiden Open Variation Database	RCV000212822	SCV001193348	pathogenic	not provided	2019-09-30	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: James Whitworth, kConFab - Heather Thorne, Marc Tischkowitz.
King Laboratory, University of Washington	RCV001171469	SCV001251380	pathogenic	Familial cancer of breast; Hereditary cancer-predisposing syndrome	2019-09-01	no assertion criteria provided	research
GenomeConnect - Invitae Patient Insights Network	RCV001535480	SCV001749413	not provided	Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3; Malignant tumor of breast		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 04-13-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
PreventionGenetics, part of Exact Sciences	RCV004528792	SCV005360544	pathogenic	PALB2-related disorder	2024-08-30	no assertion criteria provided	clinical testing	The PALB2 c.3113G>A variant is predicted to result in premature protein termination (p.Trp1038*). This variant has been reported in multiple individuals with a personal and/or family history of breast cancer (Rahman et al. 2007. PubMed ID: 17200668; Southey et al. 2010. PubMed ID: 21182766; Teo et al. 2013. PubMed ID: 23448497; Teo et al. 2013. PubMed ID: 23471749; Hartley et al. 2014. PubMed ID: 25225577). Functional studies showed that this variant alters splicing and results in three different mRNA transcripts (Casadei et al. 2011. PubMed ID: 21285249). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD and is interpreted as pathogenic in ClinVar by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/126711/). Nonsense variants in PALB2 are expected to be pathogenic. This variant is interpreted as pathogenic.